Trastuzumab Emtansine in Treating Older Patients With Human Epidermal Growth Factor Receptor 2-Positive Stage I-III Breast Cancer

PRIMARY OBJECTIVES:

I. Invasive disease-free survival (IDFS), defined as occurrence of any of the following:
ipsilateral invasive breast cancer recurrence, regional invasive breast cancer recurrence,
distant recurrence, death attributable to any cause, contralateral invasive breast cancer, or
second non-breast invasive cancer. Note: In-situ events are not included.

SECONDARY OBJECTIVES:

I. Overall survival (OS). II. Recurrence-free survival (RFS). III. Adverse events. IV.
Cardiac function/adverse events. V. Site of first recurrence.

TERTIARY OBJECTIVES:

I. The associations of adverse events and outcomes with each of the following will be
examined: geriatric assessment (GA), patient reported outcomes (Patient-Reported Outcomes
Version of the Common Terminology Criteria for Adverse Event [PRO-CTCAE]), quality of life
(QOL), and biomarkers of aging.

II. To determine whether clinician-reported CTCAEs are more accurate when PRO-CTCAE data are
shared with the patient and clinician.

III. Utilize a high-throughput mutation profiling system (Oncomap) to query a large panel of
cancer gene mutations in older patients with HER2-positive breast cancers.

OUTLINE:

Patients receive trastuzumab emtansine intravenously (IV) over 30-90 minutes on day 1.
Treatment repeats every 21 days for 17 courses in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up at 6-12 months and then yearly
for 4 years.

Inclusion Criteria:

- Confirmed HER2-positive disease by local pathology, defined as immunohistochemistry
(IHC) 3+ or amplification by fluorescent in situ hybridization (FISH) (HER2/chromosome
17 centromere [CEP17] ratio >= 2 or an average of >= 6 HER2 gene copies per nucleus)
AND confirmed by Central Pathology Review (Mayo Clinic Rochester) prior to patient
being registered to begin protocol therapy

- NOTE: ductal carcinoma in situ (DCIS) components should not be counted in the
determination of HER2 status

- Stage I-III breast cancer with the following criteria met:

- If node-negative or if node status unknown (because it was not assessed), tumor
must be > 5 mm (T1b) of any hormone receptor subtype (document estrogen
receptor/progesterone receptor [ER/PR] status: if some ER/PR staining is present,
ER and PR negative are defined as being positive in < 10% cells [per local
pathology read])

- If node-positive (N1-N3), T1mi, T1a, T1b, T1c, T2, or T3 tumors are eligible

- Definition of node-negative disease (when node status known): If the patient
has had a negative sentinel node biopsy and/or a negative axillary
dissection, then the patient is determined to be node-negative; axillary
nodes with single cells or tumor clusters =< 0.2 mm by either hematoxylin
and eosin (H&E) or IHC will be considered node-negative; any axillary lymph
node with tumor clusters between 0.02 and 0.2 cm is considered a
micrometastasis; patients with a micrometastasis are eligible; an axillary
dissection is not required to be performed in patients with a positive
sentinel node and management of the axilla will be left up to the treating
provider; in cases where the specific pathologic size of lymph node
involvement is subject to interpretation, the principal investigator will
make the final determination as to eligibility; in these special situations,
the investigator must document this approval in the patient medical record

- ER/PR determination assays performed by IHC methods according to the local institution
standard protocol

- Standard chemotherapy/trastuzumab declined by patient OR patient is deemed by
physician for any reason to not be a candidate for standard therapy (i.e. patient
and/or provider choose not to pursue standard trastuzumab-based chemotherapy regimen
because of concerns related to toxicity or patient preference)

- For patients with bilateral or multifocal/multicentric breast cancers, one of the
following criteria must be met to enroll: (1) each cancer individually meets criteria
for enrollment (only ONE tumor has to undergo central confirmation for HER2), OR (2)
at least one tumor meets eligibility (per tumor size/nodes/subtype outlined above) and
the other foci in the ipsilateral or contralateral breast are also HER2-positive but
are too small for enrollment (e.g., a patient is eligible if a cancer is T2N0 and
HER2-positive in one breast, but the contralateral breast has a T1b HER2+ cancer that
isn?t eligible on its own, OR, (3) at least one tumor meets eligibility and the other
foci in the ipsilateral or contralateral breast are HER2-negative and do not meet
criteria for adjuvant chemotherapy per provider discretion (e.g. if a patient has a
HER2-positive tumor meeting eligibility but also has a second, HER2-negative, small,
node-negative, ER+, low grade cancer present, she is still eligible for enrollment);
however, in the specific case that a second breast cancer is stage III and
HER2-negative, that patient is excluded (because the second cancer is high-risk and
likely will require non-HER2-directed therapy)

- All tumor removed by either a modified radical mastectomy or a segmental mastectomy
(lumpectomy)

- NOTE: management of axillary lymph nodes is up to the treating provider; however,
all surgical margins should be clear of invasive cancer or DCIS (i.e., no tumor
on ink); the local pathologist must document negative margins of resection in the
pathology report; if all other margins are clear, a positive posterior (deep)
margin is permitted, provided the surgeon documents that the excision was
performed down to the pectoral fascia and all tumor has been removed; likewise,
if all other margins are clear, a positive anterior (superficial; abutting skin)
margin is permitted provided the surgeon documents that all tumor has been
removed

- =< 90 days from the patient?s most recent breast surgery for this breast cancer

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2

- Baseline ejection fraction >= 50% by multi gated acquisition scan (MUGA) scan or
echocardiogram performed =< 60 days prior to registration

- Absolute neutrophil count (ANC) >= 1500/mm^3 obtained =< 14 days prior to registration

- Platelet count >= 100,000/mm^3 obtained =< 14 days prior to registration

- Hemoglobin > 9.0 g/dL obtained =< 14 days prior to registration

- Total bilirubin =< 1.5 x upper limit of normal (ULN); if patient has known Gilbert?s
syndrome, direct bilirubin =< 2.0 x ULN obtained =< 14 days prior to registration

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper
limit of normal (ULN) obtained =< 14 days prior to registration

- Alkaline phosphatase =< 2.5 x ULN obtained =< 14 days prior to registration

- International normalized ratio (INR) < 1.5 x ULN for institution unless patient is on
planned therapy with anticoagulants (i.e., warfarin) with higher target planned
obtained =< 14 days prior to registration; in those cases, INR up to 3.5 is acceptable

- Partial thromboplastin time (PTT) < 1.5 x ULN for institution unless patient is on
planned therapy with heparin or heparin-like products obtained =< 14 days prior to
registration

- Life expectancy > 5 years

- Willing to employ adequate and appropriate birth control if applicable

- NOTE: This study is for patients aged 60 and older and most female patients will
have entered menopause by this time; however patients should not become pregnant
while on this study; pre-menopausal women need to use birth control while on this
study and women should not breastfeed a baby while on this study; any man treated
on this study will also need to use contraception if his partner is a
premenopausal female; patients should check with their health care provider about
what kind of birth control methods to use and how long to use them

- Negative urine or serum pregnancy test done =< 7 days prior to
registration/randomization, for women of childbearing potential only

- NOTE: in the rare case that a woman enrolling on study is of childbearing
potential, a pregnancy test is required prior to enrollment on study

- Able to provide informed written consent

- Willing to return to consenting institution for follow-up (during the active
monitoring phase of the study)

- Willing to provide blood samples for mandatory correlative research purposes

Exclusion Criteria:

- Evidence of metastatic disease

- NOTE: patients will not require baseline staging positron emission tomography
(PET) or computed tomography (CT) chest, abdomen, pelvis or bone scan to rule out
metastatic disease prior to enrollment; any staging scans will be ordered at the
treating provider?s discretion; if metastatic disease is found on any staging
studies done, patients will not be eligible for enrollment

- Locally advanced tumors at diagnosis (T4), including tumors fixed to the chest wall,
peau d?orange, skin ulcerations/nodules, or clinical inflammatory changes (diffuse
brawny cutaneous induration with an erysipeloid)

- Patients with stage III, HER2-negative cancer in the contralateral breast

- Positive hepatitis B (hepatitis B surface antigen and antibody) and/or hepatitis C
(hepatitis C antibody test) as indicated by serologies conducted =< 3 months prior to
starting study if liver function tests are outside of the normal institutional range

- NOTE: patients with hepatitis B or C serologies indicating active infection
without known active disease must meet the eligibility requirements for ALT, AST,
total bilirubin, INR, PTT, and alkaline phosphatase on at least two consecutive
occasions, separated by at least 1 week

- Active liver disease, for example, due to autoimmune hepatic disorder, or sclerosing
cholangitis

- Significant cardiac disease or risk factors as indicated by MUGA or echocardiogram
performed =< 60 days prior to registration and/or by presence of any of the following:

- History of National Cancer Institute (NCI) Common Terminology Criteria for
Adverse Events (CTCAE) (version 4.0) grade >= 3 symptomatic congestive heart
failure (CHF) or New York Heart Association (NYHA) criteria class >= II

- Angina pectoris requiring anti-anginal medication, serious cardiac arrhythmia not
controlled by adequate medication, severe conduction abnormality, or clinically
significant valvular disease

- High-risk uncontrolled arrhythmias (i.e., atrial tachycardia with a heart rate >
100/min at rest, significant ventricular arrhythmia [ventricular tachycardia], or
higher-grade atrioventricular [AV]-block [second degree AV-block Type 2 [Mobitz
2] or third degree AV-block])

- Significant symptoms (grade >= 2) relating to left ventricular dysfunction,
cardiac arrhythmia, or cardiac ischemia

- Myocardial infarction within 12 months prior to randomization

- Uncontrolled hypertension (systolic blood pressure > 180 mmHg and/or diastolic
blood pressure >100 mmHg)

- Evidence of transmural infarction on electrocardiogram (ECG)

- Requirement for oxygen therapy

- Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment
of the investigator, would make the patient inappropriate for entry into this study or
interfere significantly with the proper assessment of safety and toxicity of the
prescribed regimens

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection or psychiatric illness/social situations that would limit compliance with
study requirements

- Currently receiving any other investigational agent which would be considered as a
treatment for the primary neoplasm

- Concurrent second malignancy or past malignancy with > 30% estimated risk of relapse
in next 5 years; EXCEPTIONS: non-melanotic skin cancer or carcinoma-in-situ of the
cervix; NOTE: if there is a history or prior malignancy, patient must not be receiving
active treatment for this malignancy cancer

- Any prior treatment with T-DM1 (trastuzumab emtansine) or any trastuzumab therapy

- Any neoadjuvant chemotherapy

- > 4 weeks of tamoxifen therapy, or other hormonal therapy, for adjuvant therapy for
this malignancy

- NOTE: if the patient has received < 4 weeks of such therapy but is still
receiving it at the time of entry into the study, patient must temporarily stop
the therapy; the therapy can re-start only after 12 weeks of T-DM1 has been
administered

- History of exposure at any time to the following cumulative doses of anthracyclines:

- Doxorubicin or liposomal doxorubicin > 500 mg/m^2

- Epirubicin > 900 mg/m^2

- Mitoxantrone >120 mg/m^2

- Another anthracycline, or more than one anthracycline used in a cumulative dose
exceeding the equivalent of doxorubicin 500 mg/m^2

- History of intolerance (including grade 3 or 4 infusion reactions) to murine proteins

- History of previous invasive breast cancer =< 5 years

- NOTE: history of DCIS, lobular carcinoma in situ (LCIS) is allowed